The study of simian immunodeficiency virus (SIV) infection in Asian macaques has provided numerous insights into the pathogenesis of AIDS in human immunodeficiency virus type 1 (HIV-1)-infected humans. The divergence of the envelope glycoproteins of SIVmac and HIV-1, however, limit the utility of the SIVmac model for studying HIV-1 envelope glycoprotein determinants of pathogenicity, and for testing vaccine strategies directed against the HIV-1 envelope glycoproteins. In vivo passage of a chimeric simian-human immunodeficiency virus (SHIV-89.6) expressing HIV-1 tat, rev, vpu and env genes generated pathogenic virus (SHIV-89.6P) inducing rapid CD4+ lymphocyte depletion and AIDS-like illness in rhesus monkeys (J Virol 70:6922-6928, 1996). Virus generated from some proviral clones of SHIV-89.6P caused a rapid and profound decline of CD4+ lymphocytes in a high percentage of inoculated macaques. Nucleotide changes potentially responsible for increased virulence of SH IV-89.6P were limited to the env, tat or long terminal repeat sequences, with most of the observed changes in env. Nucleotide changes in env altered 12 amino acids in the gp120 and gp41 exterior domains, and a 140 bp deletion in env resulted in the substitution of the carboxyl terminus of the SIVmac gp41 glycoprotein for that of the HIV-1 gp41 glycoprotein. Both the level of viremia and the structure of the HIV-1 envelope glycoprotein ectodomains individually contributed to the efficiency with which CD4+ T lymphocytes were depleted. The envelope glycoproteins of recombinant SHIVs that efficiently caused loss of CD4+ T lymphocytes exhibited increased chemokine receptor binding and membrane-fusing capacity compared with those of less pathogenic viruses. These studies identify the HIV-1 envelope glycoprotein ectodomains as determinants of CD4+ T lymphocyte loss in vivo and provide a foundation for studying pathogenic mechanisms. FUNDING Collaboration with Dr. Letvin, Harvard University PUBLICATIONS Karlsson GB, Halloran M, Schenten D, Lee J, Racz P, Tenner-Racz K, Manola J, Gelman R, Etemad-Moghadam B, Desjardins E, Wyatt R, Gerard NP, Marcon L, Margolin D, Fanton J, Axthelm MK, Letvin NL, Sodroski J. The envelope glycoprotein ectodomains determine the efficiency of CD4+ T lymphocyte depletion in simian-human immunodeficiency virus-infected macaques. J Exp Med 188(6):1159-1171, 1998.